Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis

被引:24
作者
Han, Xiaonan
Osuntokun, Bankole
Benight, Nancy
Loesch, Kimberly
Frank, Stuart J.
Denson, Lee A.
机构
[1] Univ Cincinnati, Coll Med, Cincinnati, OH USA
[2] Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA
[3] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
[5] Vet Affairs Med Ctr, Endocrinol Sect, Med Serv, Birmingham, AL USA
关键词
D O I
10.2353/ajpath.2006.060186
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) gamma suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPAR gamma abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wildtype controls, with and without rosiglitazone pretreatment. GH receptor, STAT5b, PPAR gamma, and nuclear factor kappa B activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPAR gamma expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPAR gamma nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor kappa B activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GH-dependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPAR gamma expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restoring both normal anabolic metabolism and mucosal tolerance in CD.
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页码:1999 / 2013
页数:15
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